Peripheral nerve is the only part of the nervous system that is commonly biopsied to evaluate human neurologic disease. Nerve biopsies should provide a valuable means of extending our understanding of the pathogenesis of neuropathies. To do so new, clinically appropriate methods of studying the specimens are required. This proposal will develop innovative means of examining human biopsies and apply these methods to specific questions. Aim 1 will examine the participation of macrophages in a variety of neuropathies, using high resolution immunocytochemistry of teased nerve fibers and a panel of antibodies that will allow phenotyping the macrophage response. Aim 1 will examine Schwann cells proliferation in such disorders as hypertrophic neuropathies due to Charcot-Marie-Tooth disease (HMSN I); these studies will utilize nuclear proliferation-associated monoclonal antibodies. Aim 3 will examine Schwann cell expression of nerve growth factor receptor (NGF-R) in neuropathies; we anticipate that NGF-R will be found in a variety of demyelinating disorders as well as in axonal degenerations. Aim 4 will examine the expression of growth-associated proteins in axons, asking to what extent to which they might provide an indication of early axonal disease. Aim 5 will use in situ hybridization to examine the content of mRNAs for myelin proteins in Schwann cells in selected neuropathies. We anticipate that many of the approaches developed will find widespread application in the routine examination of peripheral nerve biopsies, and others will provide tools for use in research laboratories.